升高的脂质过氧化（LPO）通常存在于肿瘤微环境（TME）中，深度影响抗癌免疫，并可作为开发新的抗肿瘤疗法的靶点。然而，肿瘤细胞也可以重构其代谢以应对升高的LPO。在这里，我们报告了一种新颖且非抗氧化机制，通过累积胆固醇让肿瘤细胞受益，以抑制LPO和铁死亡，这是一种以累积LPO为特征的非细胞凋亡形式的细胞死亡。调节胆固醇代谢，特别是LDLR介导的胆固醇摄取，改变了肿瘤细胞对铁死亡的敏感性。细胞胆固醇含量的升高特异性抑制了TME中GSH-GPX4抑制或氧化因子引起的LPO。此外，通过MβCD降低TME中的胆固醇，有效提高了小鼠异种移植模型中铁死亡的抗肿瘤效应。与其代谢中间产物的抗氧化作用不同，胆固醇的保护作用归因于其降低膜流动性和促进脂 rafts形成的能力，这影响了LPO底物的扩散。在肾癌患者的肿瘤组织中也发现了LPO和脂 rafts之间的相关性。综上所述，我们的发现确定了一种普遍且非牺牲的机制，即胆固醇抑制LPO，这可以被利用来增强基于铁死亡的抗肿瘤策略的功效。版权所有©2023年作者。由Elsevier B.V.出版，保留所有权利。

Elevated lipid peroxidation (LPO), usually present in the tumour microenvironment (TME), is profoundly implicated in antitumour immunity and may be targeted for the development of new antitumour therapies. However, tumour cells may also rewire their metabolism to survive elevated LPO. Here, we report a novel and nonantioxidant mechanism by which tumour cells benefit from accumulated cholesterol to restrain LPO and ferroptosis, a nonapoptotic form of cell death characterized by accumulated LPO. Modulating cholesterol metabolism, especially LDLR-mediated cholesterol uptake, shifted the susceptibility of tumour cells to ferroptosis. Elevation of cellular cholesterol content specifically restrained LPO triggered by GSH-GPX4 inhibition or oxidizing factors in the TME. Furthermore, depletion of TME cholesterol by MβCD efficiently enhanced the antitumour efficacy of ferroptosis in a mouse xenograft model. Distinct from the antioxidant effect of its metabolic intermediates, the protective role of cholesterol was ascribed to its ability to decrease membrane fluidity and promote lipid raft formation, which affects the diffusion of LPO substrates. A correlation between LPO and lipid rafts was also found in tumour tissues from renal cancer patients. Together, our findings have identified a general and nonsacrificial mechanism by which cholesterol suppresses LPO, which can be exploited to enhance the efficacy of ferroptosis-based antitumour strategies.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.